We propose to collect and analyze the first ever whole genome sequence data from patients with schizophrenia (SCZ, n=150), bipolar disorder (BPD, n=150) and controls (n=100). By providing the first comprehensive evaluation of genetic variation in individuals with psychiatric disease we will lay the foundation for future genetic studies of SCZ and BPD. For many common diseases, large-scale genome-wide association studies (GWAS) have recently identified new genetic risk factors, typically in previously unsuspected genes or non-coding regions. Family and twin studies have conclusively established that heritable factors play the major role in SCZ and BPD risk, and GWAS studies have pointed to important roles for rare inherited and de novo copy number variants as well as common SNPs. We will use next generation sequencing technology to obtain whole genome DNA sequence for 400 samples. Aim 1: From among the >18,000 samples for whom we have GWAS data we will select SCZ and BPD patients from a Swedish sample, enriched for family- history of disease, for whom we have matched controls, and from a US sample enriched for sporadic cases, for whom parental DNA samples are available. Perform whole genome sequencing to identify DNA variation. Aim 2: Develop an analytic framework to annotate, curate and query the genetic data with respect to disease status. Aim 3: Follow-up sequencing results, including in silico genotyping, deep sequencing of targeted regions in 3000 individuals and genotyping specific variants in over 18,000 individuals. All data and software tools will be made available as a resource to the broader community. PUBLIC HEALTH RELEVANCE: Narrative: We will obtain whole genome sequence data using next generation high-throughput technology in patients with schizophrenia and bipolar disorder and matched controls to find new genetic variation that may be associated with these diseases. They are large public health problems affecting millions of Americans and have no effective treatments.